Compositions and medical devices utilizing bioabsorbable polymeric waxes and rapamycin

ABSTRACT

The present invention is directed to medical devices and pharmaceutical or agricultural compositions, and seeds, each containing a synthetic, bioabsorbable, biocompatible polymeric wax that is the reaction product of a polybasic acid or derivative thereof, a polyol and a fatty acid, the polymeric wax having a melting point less than about 70° C., as determined by differential scanning calorimetry, and an effective amount of rapamycin or an analogue thereof.

FIELD OF THE INVENTION

The present invention relates to medical devices and compositionscontaining bioabsorbable and biocompatible polymeric waxes and rapamycinapplications.

BACKGROUND OF THE INVENTION

Both natural and synthetic polymers, including homopolymers andcopolymers, which are both biocompatible and absorbable in vivo areknown for use in the manufacture of medical devices that are implantedin body tissue and absorb over time. Examples of such medical devicesinclude suture anchor devices, sutures, staples, surgical tacks, clips,plates and screws, drug delivery devices, adhesion prevention films andfoams, and tissue adhesives.

Natural polymers may include catgut, cellulose derivatives and collagen.Natural polymers typically absorb by an enzymatic degradation process inthe body.

Synthetic polymers may include aliphatic polyesters, polyanhydrides andpoly(orthoester)s. Synthetic absorbable polymers typically degrade by ahydrolytic mechanism. Such synthetic absorbable polymers includehomopolymers, such as poly(glycolide), poly(lactide),poly(e-caprolactone), poly(trimethylene carbonate) andpoly(p-dioxanone), and copolymers, such as poly(lactide-co-glycolide),poly(e-caprolactone-co-glycolide), and poly(glycolide-co-trimethylenecarbonate). The polymers may be statistically random copolymers,segmented copolymers, block copolymers or graft copolymers.

Alkyd-type polyesters prepared by the polycondensation of a polyol,polyacid and fatty acid are used in the coating industry in a variety ofproducts, including chemical resins, enamels, varnishes and paints.These polyesters also are used in the food industry to make texturizedoils and emulsions for use as fat substitutes.

There is a great need for polymers for use in drug delivery and medicaldevices, where the polymers have both low melting temperatures and lowviscosities upon melting, thus permitting for solvent-free processingtechniques in preparation of medical devices and compositions, cancrystallize rapidly, and biodegrade within 6 months.

SUMMARY OF THE INVENTION

The present invention is directed to medical devices, pharmaceutical andagricultural compositions, and seeds, each comprising a synthetic,bioabsorbable, biocompatible polymeric wax comprising the reactionproduct of a polybasic acid or derivative thereof, a fatty acid and apolyol, the polymeric wax having a melting point less than about 70° C.,as determined by differential scanning calorimetry.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a plot of sustained release of Risperidone frompoly(monostearoyl glycerol-co-succinate) microparticles in vitro.

FIG. 2 is a plot of sustained release of Risperidone Pamoate frompoly(monostearoyl glycerol-co-succinate) microparticles in vitro.

FIG. 3 is a plot of sustained release of Risperidone Pamoate frompoly(monostearoyl glycerol-co-succinate) microparticles in vivo.

FIG. 4 is a plot of sustained release of Risperidone frompoly(monostearoyl glycerol-co-succinate) films in vitro.

FIG. 5 is a plot of sustained release of Risperidone frompoly(monostearoyl glycerol-co-succinate) cylinders in vitro.

FIG. 6 is a plot of sustained release of Albumin from Poly(monostearoylglycerol-co-succinate) in vitro.

DETAILED DESCRIPTION OF THE INVENTION

Alkyd polymers have been prepared by several known methods. For example,alkyd-type polymers were prepared by Van Bemmelen (J. Prakt. Chem., 69(1856) 84) by condensing succinic anhydride with glycerol. In the “FattyAcid” method (see Parkyn, et al. Polyesters (1967), Iliffe Books,London, Vol. 2 and Patton, In: Alkyd Resins Technology,Wiley-Interscience New York (1962)), a fatty acid, a polyol and ananhydride are mixed together and allowed to react. The “FattyAcid-Monoglyceride” method includes a first step of esterifying thefatty acid with glycerol and, when the first reaction is complete,adding an acid anhydride. The reaction mixture then is heated and thepolymerization reaction takes place. In the “Oil-Monoglyceride” method,an oil is reacted with glycerol to form a mixture of mono-, di-, andtriglycerides. This mixture then is polymerized by reacting with an acidanhydride.

The synthetic, bioabsorbable, biocompatible polymeric waxes utilized inthe present invention are the reaction product of a polybasic acid orderivative thereof, a fatty acid, and a polyol, and may be classified asalkyd polyester waxes. As used herein, a wax is a solid, low-meltingsubstance that is plastic when warm and, due to its relatively lowmolecular weight, is fluid when melted. Preferably, the polymeric waxesof the present invention are prepared by the polycondensation of apolybasic acid or derivative thereof and a monoglyceride, wherein themonoglyceride comprises reactive hydroxy groups and fatty acid groups.The expected hydrolysis byproducts are glycerol, dicarboxylic acid(s),and fatty acid(s), all of which are biocompatible. Preferably, thepolymeric waxes utilized in the present invention will have a numberaverage molecular weight between about 1,000 g/mole and about 100,000g/mole, as determined by gel permeation chromatography. The polymericwaxes comprise an aliphatic polyester backbone with pendant fatty acidester groups that crystallize rapidly, depending on the fatty acid chainlength, and exhibit relatively low melting points, e.g. less than about100° C., preferably less than about 70° C. More preferably, the meltingpoint of the polymeric wax will be between about 25° C. and about 70° C.Typically, the polymeric waxes used in the present invention will be asolid at room temperature.

Fatty acids used to prepare polymeric waxes utilized in the presentinvention may be saturated or unsaturated and may vary in length fromC₁₄ to C₃₀. Examples of such fatty acids include, without limitation,stearic acid, palmitic acid, myrisitic acid, caproic acid, decanoicacid, lauric acid, linoleic acid and oleic acid.

Polyols that can be used to prepare the polymeric waxes include, withoutlimitation, glycols, polyglycerols, polyglycerol esters, glycerol,sugars and sugar alcohols. Glycerol is a preferred polyhydric alcoholdue to its abundance and cost.

Monoglycerides which may be used to prepare polymeric waxes utilized inthe present invention include, without limitation, monostearoylglycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproylglycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoylglycerol, monooleoyl glycerol, and combinations thereof. Preferredmonoglycerides include monostearoyl glycerol, monopalmitoyl glycerol andmonomyrisitoyl glycerol.

Polybasic acids that can be used include natural multifunctionalcarboxylic acids, such as succinic, glutaric, adipic, pimelic, suberic,and sebacic acids; hydroxy acids, such as diglycolic, malic, tartaricand citric acids; and unsaturated acids, such as fumaric and maleicacids. Polybasic acid derivatives include anhydrides, such as succinicanhydride, diglycolic anhydride, glutaric anhydride and maleicanhydride, mixed anhydrides, esters, activated esters and acid halides.The multifunctional carboxylic acids listed above are preferred.

In certain embodiments of the invention, the polymeric wax may beprepared from the polybasic acid or derivative thereof, themonoglyceride and, additionally, at least on additional polyol selectedfrom the group consisting of ethylene glycol, 1,2-propylene glycol,1,3-propanediol, bis-2-hydroxyethyl ether, 1,4-butanediol,1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol,1,12-dodecanediol, other diols, linear poly(ethylene glycol), branchedpoly(ethylene glycol), linear poly(propylene glycol), branchedpoly(propylene glycol), linear poly(ethylene-co-propylene glycol)s andbranched poly(ethylene-co-propylene glycol)s.

In preparing the polymeric waxes utilized in the present invention, theparticular chemical and mechanical properties required of the polymericwax for a particular use must be considered. For example, changing thechemical composition can vary the physical and mechanical properties,including absorption times. Copolymers can be prepared by using mixturesof diols, triol, polyols, diacids, triacids, and different monoalkanoylglycerides to match a desired set of properties. Similarly, blends oftwo or more alkyd polyesters may be prepared to tailor properties fordifferent applications.

Alkyd polyester waxes of the present invention can be made morehydrophobic by increasing the length of the fatty acid side chain or thelength of the diacid in the backbone, or by incorporating a long chaindiol. Alternatively, alkyd polyester waxes of the present invention canbe made more hydrophilic or amphiphilic by employing hydroxy acids, suchas malic, tartaric and citric acids, or some oxadiacids, in thecomposition, or by employing poly(ethylene glycol)s or copolymers ofpolyethylene glycol and polypropylene glycol, commonly known asPluronics, in the formation of segmented block copolymers.

Copolymers containing other linkages in addition to an ester linkagealso may be synthesized; for example, ester-amides, ester-carbonates,ester-anhydrides and ester urethanes, to name a few.

Multifunctional monomers may be used to produce cross-linked polymericwax networks. Alternatively, double bonds may be introduced by usingpolyols, polyacids or fatty acids containing at least one double bond toallow photocrosslinking. Hydrogels may be prepared using this approachprovided the polymer is sufficiently water soluble or swellable.

Functionalized polymeric waxes can be prepared by appropriate choice ofmonomers. Polymers having pendant hydroxyls can be synthesized using ahydroxy acid such as malic or tartaric acid in the synthesis. Polymerswith pendent amines, carboxyls or other functional groups also may besynthesized. A variety of biological active substances, hereinafterreferred to as bioactive agents, can be covalently attached to thesefunctional polymeric waxes by known coupling chemistry to give sustainedrelease of the bioactive agent. As used herein, bioactive agent is meantto include those substances or materials that have a therapeutic effecton mammals, e.g. pharmaceutical compounds, or an adverse affect on, e.g.insects and fungi, such as pesticides, insecticides, fungicides,herbicides and germicides, as well as substances or materials used toenhance growth of plants, e.g. fertilizers.

One skilled in the art, once having the benefit of the disclosureherein, will be able to ascertain particular properties of the polymericwaxes required for particular purposes, and readily prepare polymericwaxes that provide such properties.

The polymerization of the alkyd polyester preferably is performed undermelt polycondensation conditions in the presence of an organometalliccatalyst at elevated temperatures. The organometallic catalystpreferably is a tin-based catalyst e.g. stannous octoate. The catalystpreferably will be present in the mixture at a mole ratio of polyol andpolycarboxylic acid to catalyst in the range of from about 15,000/1 to80,000/1. The reaction preferably is performed at a temperature no lessthan about 120° C. Higher polymerization temperatures may lead tofurther increases in the molecular weight of the copolymer, which may bedesirable for numerous applications. The exact reaction conditionschosen will depend on numerous factors, including the properties of thepolymer desired, the viscosity of the reaction mixture, and meltingtemperature of the polymer. The preferred reaction conditions oftemperature, time and pressure can be readily determined by assessingthese and other factors.

Generally, the reaction mixture will be maintained at about 180° C. Thepolymerization reaction can be allowed to proceed at this temperatureuntil the desired molecular weight and percent conversion is achievedfor the copolymer, which typically will take from about 15 minutes to 24hours. Increasing the reaction temperature generally decreases thereaction time needed to achieve a particular molecular weight.

In another embodiment, copolymers of alkyd polyesters can be prepared byforming an alkyd polyester prepolymer polymerized under meltpolycondensation conditions, then adding at least one lactone monomer orlactone prepolymer. The mixture then would be subjected to the desiredconditions of temperature and time to copolymerize the prepolymer withthe lactone monomers. The molecular weight of the prepolymer, as well asits composition, can be varied depending on the desired characteristicthat the prepolymer is to impart to the copolymer. Those skilled in theart will recognize that the alkyd polyester prepolymers described hereincan also be made from mixtures of more than one diol or dioxycarboxylicacid.

The polymers, copolymers and blends of the present invention can becross-linked to affect mechanical properties. Cross-linking can beaccomplished by the addition of cross-linking enhancers, irradiation,e.g. gamma-irradiation, or a combination of both. In particular,cross-linking can be used to control the amount of swelling that thematerials of this invention experience in water.

One of the beneficial properties of the alkyd polyester of thisinvention is that the ester linkages are hydrolytically unstable, andtherefore the polymer is bioabsorbable because it readily breaks downinto small segments when exposed to moist body tissue. In this regard,while it is envisioned that co-reactants could be incorporated into thereaction mixture of the polybasic acid and the diol for the formation ofthe alkyd polyester, it is preferable that the reaction mixture does notcontain a concentration of any co-reactant which would render thesubsequently prepared polymer nonabsorbable. Preferably, the reactionmixture is substantially free of any such co-reactants if the resultingpolymer is rendered nonabsorbable.

In one embodiment of the invention, the alkyd polyester waxes of thepresent invention can be used as a pharmaceutical carrier in a drugdelivery matrix. To form the matrix, the polymeric wax would be mixedwith an effective amount of a therapeutic agent to form the matrix. Thevariety of therapeutic agents that can be used in conjunction with thepolymeric wax of the invention is vast. In general, therapeutic agentswhich may be administered via pharmaceutical compositions of theinvention include, without limitation, antiinfectives, such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilators,including general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones, such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives, including rapamycin oran analogue thereof; muscle relaxants; parasympatholytics;psychostimulants; sedatives; tranquilizers; naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins; oligonucleotides, antibodies, antigens, cholinergics,chemotherapeutics, hemostatics, clot dissolving agents, radioactiveagents and cystostatics.

The drug delivery matrix may be administered in any suitable dosage formsuch as oral, parenteral, subcutaneously as an implant, vaginally or asa suppository. Matrix formulations containing the alkyd polyester may beformulated by mixing one or more therapeutic agents with the polymericwax. The therapeutic agent may be present as a liquid, a finely dividedsolid, or any other appropriate physical form. Typically, butoptionally, the matrix will include one or more additives, such as, butnot limited to, nontoxic auxiliary substances such as diluents,carriers, excipients, stabilizers or the like. Other suitable additivesmay be formulated with the polymeric wax and pharmaceutically activeagent or compound.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001% to about 70%, more typically about0.001% to about 50%, most typically about 0.001% to about 20% by weightof the matrix.

The quantity and type of alkyd polyester wax incorporated into theparenteral will vary depending on the release profile desired and theamount of drug employed. The product may contain blends of polyesters toprovide the desired release profile or consistency to a givenformulation.

The alkyd polyester wax, upon contact with body fluids including bloodor the like, undergoes gradual degradation, mainly through hydrolysis,with concomitant release of the dispersed drug for a sustained orextended period, as compared to the release from an isotonic salinesolution. This can result in prolonged delivery, e.g. over about 1 toabout 2,000 hours, preferably about 2 to about 800 hours) of effectiveamounts, e.g. 0.0001 mg/kg/hour to 10 mg/kg/hour) of the drug. Thisdosage form can be administered as is necessary depending on the subjectbeing treated, the severity of the affliction, the judgment of theprescribing physician, and the like.

Individual formulations of drugs and alkyd polyester wax may be testedin appropriate in vitro and in vivo models to achieve the desired drugrelease profiles. For example, a drug could be formulated with an alkydpolyester wax and orally administered to an animal. The drug releaseprofile could then be monitored by appropriate means, such as by takingblood samples at specific times and assaying the samples for drugconcentration. Following this or similar procedures, those skilled inthe art will be able to formulate a variety of formulations.

In addition to compositions comprising therapeutic agents as set forthabove, compositions according to the present invention also may comprisebioactive agents that are toxic to certain life forms, e.g. pesticides,insecticides, fungicides, herbicides and germicides, as well asfertilzers. In one embodiment of the invention, seeds may be coated withcompositions comprising the polymeric waxes, with or without suchbioactive agents present in the composition.

In a further embodiment of the present invention the polymeric waxes andblends thereof can be used in tissue engineering applications, e.g. assupports for cells. Appropriate tissue scaffolding structures are knownin the art, such as the prosthetic articular cartilage described in U.S.Pat. No. 5,306,311, the porous biodegradable scaffolding described in WO94/25079, and the prevascularized implants described in WO 93/08850 (allhereby incorporated by reference herein). Methods of seeding and/orculturing cells in tissue scaffoldings are also known in the art such asthose methods disclosed in EPO 422 209 B1, WO 88/03785, WO 90/12604 andWO 95/33821 (all hereby incorporated by reference herein).

The polymers of this invention can be melt processed by numerous methodsto prepare a vast array of useful devices. These polymers can beinjection or compression molded to make implantable medical and surgicaldevices, especially wound closure devices. The preferred wound closuredevices are surgical clips, staples and sutures.

Alternatively, the alkyd polyester waxes can be extruded to preparefilaments. The filaments thus produced may be fabricated into sutures orligatures, attached to surgical needles, packaged, and sterilized byknown techniques. The polymers of the present invention may be spun asmultifilament yarn and woven or knitted to form sponges or gauze, (ornon-woven sheets may be prepared) or used in conjunction with othermolded compressive structures as prosthetic devices within the body of ahuman or animal where it is desirable that the structure have hightensile strength and desirable levels of compliance and/or ductility.Useful embodiments include tubes, including branched tubes, for artery,vein or intestinal repair, nerve splicing, tendon splicing, sheets fortyping up and supporting damaged surface abrasions, particularly majorabrasions, or areas where the skin and underlying tissues are damaged orsurgically removed.

Additionally, the polymers can be molded to form films which, whensterilized, are useful as adhesion prevention barriers. Anotheralternative processing technique for the polymers of this inventionincludes solvent casting, particularly for those applications where adrug delivery matrix is desired.

In more detail, the surgical and medical uses of the filaments, films,and molded articles of the present invention include, but are notlimited to, knitted products, woven or non-woven, and molded productsincluding, but not limited to burn dressings, hernia patches, meshes,medicated dressings, fascial substitutes, gauze, fabric, sheet, felt orsponge for liver hemostasis, gauze bandages, arterial graft orsubstitutes, bandages for skin surfaces, suture knot clip, orthopedicpins, clamps, screws, and plates, clips, e.g. for vena cava, staples,hooks, buttons, and snaps, bone substitutes, e.g. as mandibleprosthesis, intrauterine devices, e.g. as spermicidal devices, drainingor testing tubes or capillaries, surgical instruments, vascular implantsor supports, e.g. stents or grafts, or combinations thereof, vertebraldiscs, extracorporeal tubing for kidney and heart-lung machines,artificial skin, and supports for cells in tissue engineeringapplications.

In another embodiment, the polymeric wax is used to coat a surface of asurgical article to enhance the lubricity of the coated surface. Thepolymer may be applied as a coating using conventional techniques. Forexample, the polymer may be solubilized in a dilute solution of avolatile organic solvent, such as acetone, methanol, ethyl acetate ortoluene, and then the article can be immersed in the solution to coatits surface. Once the surface is coated, the surgical article can beremoved from the solution where it can be dried at an elevatedtemperature until the solvent and any residual reactants are removed.

Although it is contemplated that numerous surgical articles, includingbut not limited to endoscopic instruments, can be coated with thepolymeric waxes of this invention to improve the surface properties ofthe article, the preferred surgical articles are surgical sutures andneedles. The most preferred surgical article is a suture, mostpreferably attached to a needle. Preferably, the suture is a syntheticabsorbable suture. These sutures are derived, for example, fromhomopolymers and copolymers of lactone monomers such as glycolide,lactide, including L-lactide D-lactide, meso-lactide and rac-lactide,ε-caprolactone, p-dioxanone, 1,4-dioxanone, 1,4-dioxepan-2-one,1,5-dioxepan-2-one and trimethylene carbonate. The preferred suture is abraided multifilament suture composed of polyglycolide orpoly(glycolide-co-lactide).

The amount of coating polymer to be applied on the surface of a braidedsuture can be readily determined empirically, and will depend on theparticular copolymer and suture chosen. Ideally, the amount of coatingcopolymer applied to the surface of the suture may range from about 0.5to about 30 percent of the weight of the coated suture, more preferablyfrom about 1.0 to about 20 weight percent, most preferably from 1 toabout 5 weight percent. If the amount of coating on the suture weregreater than about 30 weight percent, then it may increase the risk thatthe coating may flake off when the suture is passed through tissue.

Sutures coated with the polymers of this invention are desirable becausethey have a more slippery feel, thus making it easier for the surgeon toslide a knot down the suture to the site of surgical trauma. Inaddition, the suture is more pliable, and therefore is easier for thesurgeon to manipulate during use. These advantages are exhibited incomparison to sutures which do not have their surfaces coated with thepolymer of this invention.

In another embodiment of the present invention when the article is asurgical needle, the amount of coating applied to the surface of thearticle is an amount which creates a layer with a thickness rangingpreferably between about 2 to about 20 microns on the needle, morepreferably about 4 to about 8 microns. If the amount of coating on theneedle were such that the thickness of the coating layer was greaterthan about 20 microns, or if the thickness was less than about 2microns, then the desired performance of the needle as it is passedthrough tissue may not be achieved.

In yet another embodiment, the medical device comprises a bonereplacement material comprising the polymeric wax and an inorganicfiller. The organic filler may be selected from alpha-tricalciumphosphate, beta-tricalcium phosphate, calcium carbonate, bariumcarbonate, calcium sulfate, barium sulfate, hydroxyapatite, and mixturesthereof. In certain embodiments the inorganic filler comprises apolymorph of calcium phosphate. Preferably, the inorganic filler ishydroxyapatite. The bone replacement materials may further comprise atherapeutic agent in a therapeutically effective amount, such a growthfactor, to facilitate growth of bone tissue. Furthermore, the bonereplacement material may comprise a biologically derived substanceselected from the group consisting of demineralized bone, platelet richplasma, bone marrow aspirate and bone fragments. The relative amounts ofpolymeric wax and inorganic filler may be determined readily by oneskilled in the art by routine experimentation after having the benefitof this disclosure.

The examples set forth below are for illustration purposes only, and arenot intended to limit the scope of the claimed invention in any way.Numerous additional embodiments within the scope and spirit of theinvention will become readily apparent to those skilled in the art.

In the examples below, the synthesized polymeric waxes werecharacterized via differential scanning calorimetry (DSC), gelpermeation chromatography (GPC), and nuclear magnetic resonance (NMR)spectroscopy. DSC measurements were performed on a 2920 ModulatedDifferential Scanning Calorimeter from TA Instruments using aluminumsample pans and sample weights of 5-10 mg. Samples were heated from roomtemperature to 100° C. at 10° C./minute; quenched to −40° C. at 30°C./minute followed by heating to 100° C. at 10° C./minute. For GPC, aWaters System with Millennium 32 Software and a 410 Refractive IndexDetector were used. Molecular weights were determined relative topolystyrene standards using THF as the solvent. Proton NMR was obtainedin deuterated chloroform on a 400 MHz NMR spectrometer using Variansoftware.

EXAMPLE 1 Synthesis of Poly(monostearoyl glycerol-co-succinate)

8.0 gms (22.3 mmoles) of monostearoyl glycerol was added to a dry 50 mL,single neck, round bottom flask. A stir bar was added and a nitrogeninlet adapter was attached. The reaction flask was placed in a roomtemperature oil bath and a nitrogen gas blanket was started. The flaskwas heated to 140° C., and 4.46 gms (44.6 mmoles) of succinic anhydridewas added. The temperature was raised to 200° C. and maintained for 3hours. After 3 hours the flask was removed from the oil bath to cool toroom temperature. Once the solution crystallized, it was deglassed andcleaned of any glass fragments. The polymer was an amber colored solid.

DSC measurements found a melt temperature of 46.84° C., and a specificheat of 63.57 J/gm. GPC measurement determined a number averagemolecular weight of 2,688, and a weight average molecular weight of5,848. The ¹H NMR showed the following peaks: δ 0.86 triplet (3H), 1.26multiplet (28H), 1.61 multiplet (2H), 2.30 multiplet (2H), 2.65multiplet (4H), 4.16 multiplet (2H), 4.34 multiplet (2H), and 5.28multiplet (2H).

EXAMPLE 2 Synthesis of Poly(monostearoyl glycerol-co-succinate)

The same procedure as Example 1 was used, except the reaction wasmaintained at 200° C. for 22.5 hours.

DSC measurements found a melt temperature of 48.41° C., and a specificheat of 73.98 J/gm. GPC measurement determined a number averagemolecular weight of 2,546, and a weight average molecular weight of43,002. The ¹H NMR showed the same peaks as shown in Example 1.

EXAMPLE 3 Synthesis of poly(monostearoyl glycerol-co-succinate) with 5%PEG

9.50 gm (26.49 mmoles) of monostearoyl-rac-glycerol and 247.5 uL (1.39mmoles) of polyethylene glycol (Mw=200) were added to a dry 50 mL,single neck, round bottom flask. A stir bar was added and a nitrogeninlet adapter was attached. The flask was placed in a room temperatureoil bath and a nitrogen flow was started. The temperature was raised to140° C. Once at 140° C., 2.79 gm (27.89 mmoles) of succinic anhydridewas added and the temperature was raised to 200° C. The top of thereactor was wrapped with heat tape. The reaction was kept at 200° C. for21 hours. The reaction was removed from the oil bath and allowed tocool. Once the polymer crystallized, it was deglassed and cleaned of allglass pieces. The polymer was a light brown solid.

DSC measurements found a glass transition temperature of −33.59° C. amelt temperature of 50.42° C., and a specific heat of 85.18 J/gm. GPCmeasurement determined a number average molecular weight of 2,397, and aweight average molecular weight of 36,197. The ¹H NMR showed thefollowing peaks: δ 0.86 triplet (3H); 1.28 multiplet (28); 1.61multiplet (2H); 2.32 multiplet (2H); 2.66 multiplet (4H); 4.14 multiplet(2H); 4.34 multiplet (2H); 5.27 multiplet (1H).

EXAMPLE 4 Synthesis of poly(monostearoyl glycerol-co-succinate) w/5% PEG

The same procedure as Example 3 was followed, except the reaction waskept at 200° C. for 3 hours.

DSC measurements found a glass transition temperature of 7.52° C., amelt temperature of 50.86° C., and a specific heat of 70.55 J/gm. GPCmeasurement determined a number average molecular weight of 1,828, and aweight average molecular weight of 3,855. The ¹H NMR showed the samepeaks as shown in Example 4.

EXAMPLE 5 Synthesis of poly(monostearoyl glycerol-co-adipate)

20.01 gm (56.0 mmoles) of monostearoyl glycerol, 8.19 g (56.0 mmole)adipic acid and 11 μL of stannous octoate were added to a dry 100 mL,single neck, round bottom flask. A stirbar was added and a nitrogeninlet adapter was attached. The reaction flask was placed into a roomtemperature oil bath and a nitrogen blanket was applied. The flask washeated to 170° C. and held at this temperature for 24 hours. The flaskwas removed from the oil bath and allowed to cool to room temperature.The polymer was a brown solid. It was isolated by breaking the glass andcleaning off any glass fragments with a brush.

GPC measurement determined a number average molecular weight of 2000,and a weight average molecular weight of 6000. The ¹H NMR showed thefollowing peaks: δ 0.86 triplet (3H), 1.26 multiplet (28H), 1.65multiplet (6H), 2.35 multiplet (6H), 4.16 multiplet (2H), 4.34 multiplet(1H), 5.28 multiplet (2H).

EXAMPLE 6 Synthesis of poly(monostearoyl glycerol-co-glutarate)

20.0 gm (56.0 mmoles) of monostearoyl glycerol, 7.40 gm (56 mmole)glutaric acid, and 11 μL of stannous octoate were added to a dry 100 mL,single neck, round bottom flask. A stir bar was added and a nitrogeninlet adapter was attached. The reaction flask was placed in a roomtemperature oil bath and a constant a nitrogen gas blanket was applied.The reaction was heated to 170° C. and held at this temperature for 24hours. The flask was removed from the oil bath and allowed to cool toroom temperature. Once the solution crystallized, it was deglassed andcleaned of any glass fragments. The solid was dark brown.

DSC measurements found a melt temperature of 52.41° C., and a specificheat of 76.14 J/gm. GPC measurement determined a number averagemolecular weight of 2100, and a weight average molecular weight of 8800.The ¹H NMR showed the following peaks: δ 0.86 triplet (3H), 1.26multiplet (28H), 1.61 multiplet (4H), 1.95 multiplet (2H), 2.32multiplet (2H), 2.45 multiplet (4H), 4.16 multiplet (2H), 4.34 multiplet(1H), 5.28 multiplet (2H).

EXAMPLE 7 Sustained Release of Risperidone from Poly(monostearoylglycerol-co-succinate) Microparticles in vitro

Poly(monostearoyl glycerol-co-succinate) polymer was prepared asdescribed in Example 2. 10 gms of the polymer was placed in a 50 mLbeaker and heated to 110° C. to melt the polymer. 3.34 gms of a drug inthe form of a powder, Risperidone, sold by Janssen Pharmaceutica Inc.,Beerse, Belgium, under the tradename RISPERDAL, was dispersed andsuspended into the polymer melt using a magnetic stirrer to form a 25%drug in polymer blend. A gradient heating mechanism was used to limitthe exposure of the drug to the polymer melt at elevated temperature tofew seconds.

The drug/polymer blend was converted to drug/polymer microparticles on arotating disk apparatus. The drug/polymer blend first was equilibratedto 110° C. and then fed at a controlled rate of 3.5 gms/sec to thecenter of a 4-inch rotary disk that was run at 8000 RPM. The disksurface was heated using an induction heating mechanism to 130° C. toensure that the drug/polymer blend was in a liquid state on the surfaceof the disk. The rotation of the disk caused a thin liquid film ofdrug/polymer blend to be formed on the surface the disk. The liquid filmwas thrown radially outward from the surface of the disk and dropletssolidified upon contact with nitrogen in the rotating disk apparatuschamber to form drug/polymer microparticles. The processing was doneunder a nitrogen blanket to prevent polymer degradation at elevatedtemperatures. The solid microparticles were then collected using acyclone separator. The microparticles made using this process had a meanparticle size of about 100 μm.

In vitro release studies were performed with these microparticles in abuffer medium under physiological conditions. Approximately 20 mg ofmicroparticles were placed in 50 mL test tubes. 30 ml of phosphatebuffered saline solution was added to the test tubes. The test tubeswere placed in a constant temperature water bath, and kept at 37° C. forthe duration of the test. To determine drug release from themicroparticles at each time point, 5 mL of buffer was removed andfiltered through a 0.2 μm filter. The amount of drug released wasdetermined by HPLC measurements on an HP1100 instrument againstrisperidone standards.

In vitro release from the 25% drug in polymer microparticles is shown onFIG. 1. The figure shows 80% of the drug is released over a seven-dayperiod.

EXAMPLE 8 Sustained Release of Risperidone Pamoate fromPoly(monostearoyl glycerol-co-succinate) Microparticles in vitro

Poly(monostearoyl glycerol-co-succinate) polymer was prepared asdescribed in Example 2. Appropriate amounts of polymer were melted asdescribed in Example 7, and blended with amounts of a drug, RisperidonePamoate, as described in Example 8, to form 25% and 32% drug in polymerblends.

The drug/polymer blend was converted to drug/polymer microparticles on arotating disk apparatus and in vitro release studies were performed withthese microparticles in a buffer medium at physiological conditions asdescribed in Example 7. Release from the 25% and 32% drug in polymermicroparticles is shown on FIG. 2. The figure shows an approximaterelease of 60 and 25% of the drug over a seven-day period for 25% and32% drug in polymer microparticles, respectively.

EXAMPLE 9 Sustained Release of Risperidone Pamoate fromPoly(monostearoyl glycerol-co-succinate) Microparticles in vivo

A single dose intramuscular pharmacokinetic study was performed inBeagle dogs using Risperidone Pamoate from poly(monostearoylglycerol-co-succinate) microparticles. The animals utilized in thisstudy were handled and maintained in accordance with currentrequirements of the Animal Welfare Act. Compliance with the above PublicLaws was accomplished by adhering to the Animal Welfare regulations (9CFR) and conforming to the current standards promulgated in the Guidefor the Care and Use of Laboratory Animals.

25% and 32% drug in polymer microparticles were formed as described inExample 8. The microparticles were administered at a 5 mg/kg dose usingan aqueous vehicle (hyaluronic acid) for injection. The mean plasmaconcentration values as a function of time were determined via HPLC.

The mean plasma concentration values as a function of time are shown inFIG. 3. Therapeutic levels are reached at 10 ng/mL. The figure showsthat the 25% drug in polymer microparticles did not give a drug burstand provided 30 days of sustained release at therapeutic levels. The 32%drug in polymer microparticles appeared to give a small burst followedby over 21 days of sustained release at therapeutic levels.

EXAMPLE 10 Sustained Release of Risperidone from Poly(monostearoylglycerol-co-succinate) Films in vitro

Poly(monostearoyl glycerol-co-succinate) polymer was prepared asdescribed in Example 2. 10 gms of the polymer was placed in a 50 mLbeaker, and heated to 110° C. to melt the polymer. 4.25 gms ofRisperidone drug in the form of a powder was dispersed and suspendedinto the polymer melt using a magnetic stirrer to form a 30% drug inpolymer blend.

Films were prepared by melt compression of the drug/polymer blend usinga Carver laboratory press (Model #2696 Fred S. Carver Inc., MenomoneeFalls, Wis.). A 4″×4″×0.03″ sheet of poly(tetrafluoroethylene), or PTFE,was placed on the bottom platen of the press. Approximately 2-gms ofpolymer blend was placed on the PTFE sheet. 250 μm metal shims wereplaced around the blend to control the thickness of the polymer blendfilm. The polymer blend and shims were covered with another 4″×4″×0.03″sheet of PTFE. The platen temperature was raised to 80° C. which isabove the melt temperature of the polymer. The compression pressure wasin the range of 1000-2000 psi and the hold time was 5 minutes. After 5minutes, the system was cooled by circulating water around thecompression mold.

The compression molded polymer blend films were then cut into specimensof approximately 1-cm×1-cm×250 μm. Release studies were performed with20 mg film specimens in a buffer medium at physiological conditions asdescribed in Example 7. Release from 30% drug in polymer films is shownon FIG. 4. The figure shows an approximate release of 40% of the drugover a four-week period for 30% drug in polymer films.

EXAMPLE 11 Sustained Release of Risperidone from Poly(monostearoylglycerol-co-succinate) Cylinders in vitro

Poly(monostearoyl glycerol-co-succinate) polymer was prepared asdescribed in Example 2. 8.0 gms of the polymer was placed in a 50 mLbeaker, and heated to 110° C. to melt the polymer. 2 gms of Risperidonedrug in the form of a powder was dispersed and suspended into thepolymer melt using a magnetic stirrer under a nitrogen blanket to form a20% drug in polymer blend.

The molten polymer/drug mixture was aspirated into capillary tubes withan inner diameter of 1 mm, and allowed to solidify at room temperature.The capillary tube was then quenched in liquid nitrogen for 1 to 2minutes. Following quenching, the solidified cylinder was pushed out ofthe capillary tube using a metal rod. The cylinder was kept under vacuumfor 48 hrs to remove any residual moisture and then cut into cylindricalspecimens with dimensions of approximately 1 mm diameter by 1-cm lengthfor drug release studies.

Release studies were performed with these 20 mg cylindrical specimens ina buffer medium at physiological conditions as described in Example 7.Release from 20% drug in polymer cylinders is shown on FIG. 5. Thefigure shows an approximate release of 40% of the drug over a four-weekperiod for 20% drug in polymer cylinders.

EXAMPLE 12 Sustained Release of Albumin from Poly(monostearoylglycerol-co-succinate) in vitro

Poly(monostearoyl glycerol-co-succinate) polymer was prepared asdescribed in Example 1. 0.5 gms of the polymer was placed in a 5 mL vialand heated to 50° C. in an oil bath to melt the polymer. Separately,0.05 gms of Bovine serum albumin (BSA), obtained from Sigma, St. Louis,Mo., was dissolved in 1 mL of deionized water to obtain a BSA solution.The melted microdispersion was removed from the oil bath, and 50 μL ofthe BSA solution was added to the melted microdispersion. The BSAsolution/microdispersion melt mixture was stirred thoroughly by handwith a spatula until the mixture solidified. 3 mL of phosphate bufferedsaline (PBS) was added to the vial which was then transferred to a waterbath maintained at 37° C.

At each time point, the PBS was removed completely and filtered througha 0.2 μm filter. The absorbance of the sample at 280 nm was measured onan HP8453 UV spectrophotometer against albumin standards.

Release from the BSA/polymer specimens is shown on FIG. 6. The figureshows release of approximately 80% of the BSA over a four-week period.

EXAMPLE 13 Sustained Release of Rapamycin from Poly(monostearoylglycerol-co-succinate) Microparticles in vitro

Poly(monostearoyl glycerol-co-succinate) polymer was prepared asdescribed in Example 2. 10 gms of the polymer was placed in a 50 mLbeaker and heated to 110° C. to melt the polymer. 0.50 gms of a drug inthe form of a powder, rapamycin, sold by LC Labs (Woburn, Mass.), wasdispersed and suspended into the polymer melt using a magnetic stirrerto form a 5 percent drug in polymer blend. A gradient heating mechanismwas used to limit the exposure of the drug to the polymer melt atelevated temperature to few seconds.

The drug/polymer blend was converted to drug/polymer microparticles on arotating disk apparatus as described in Example 7, except that the4-inch rotary disk was run at 6500 RPM. The microparticles made usingthis process were fractionated using stacked vibratory sieves and themajority were harvested between the 75-106 micron screens and 106-150micron screens.

Drug content in 3 mg samples of microspheres was measured dissolving themicrospheres in 10 mL hexane and analyzing the solutions on an HP 1100HPLC against rapamycin standards. Drug content was determined to be5.0±0.5 percent. Due to the very low aqueous solubility of rapamycin, invitro release studies were performed with these microparticles in a25/75 ethanol/water elution medium. Approximately 3 mg of microparticleswere placed in 50 mL test tubes. 30 mL of elution solution was added tothe test tubes. This volume of solution was sufficient to dissolve 100times the mass of drug loaded into each tube. The test tubes were placedin a constant temperature water bath, and kept at 37° C. for theduration of the test. To determine drug release from the microparticlesat each time point, 1.5 mL of eluting solution was removed and filteredthrough a 0.2 mm filter. The amount of drug released was determined byHPLC measurements on an HP1100 instrument against rapamycin standards.Measurements were performed in duplicate. Averaged results over a 7 dayperiod are tabulated below. An equivalent (to what was in the drugloaded microspheres) mass of free rapamycin added to this elution mediumcompletely dissolves in less than 24 hours. 75-106 mm 106-150 mmparticle fraction particle fraction Hours % Release % Released 24 12 996 27 24 168 34 30

1. A medical device, comprising: an effective amount of rapamycin or ananalogue thereof, and a synthetic, bioabsorbable, biocompatiblepolymeric wax comprising the reaction product of a polybasic acid orderivative thereof, a fatty acid; and a polyol, said polymeric waxhaving a melting point less than about 70° C., as determined bydifferential scanning calorimetry.
 2. The medical device of claim 1wherein said polymeric wax comprises the reaction product of saidpolybasic acid or derivative thereof and a monoglyceride, saidmonoglyceride comprising the reaction product of said fatty acid andsaid polyol.
 3. The medical device of claim 2 wherein said polybasicacid or derivative thereof is selected from the group consisting ofsuccinic acid, succinic anhydride, malic acid, tartaric acid, citricacid, diglycolic acid, diglycolic anhydride, glutaric acid, glutaricanhydride, adipic acid, pimelic acid, suberic acid, sebacic acid,fumaric acid, maleic acid, maleic anhydride, mixed anhydrides, esters,activated esters and acid halides.
 4. The medical device of claim 2wherein said monoglyceride is selected from the group consisting ofmonostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol,monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol,monolinoleoyl glycerol and monooleoyl glycerol.
 5. The medical device ofclaim 4 wherein said polybasic acid derivative is succinic anhydride. 6.The medical device of claim 1 wherein said polymeric wax has a numberaverage molecular weight between about 1,000 g/mole and about 100,000g/mole, as measured by gel permeation chromatography using polystyrenestandards.
 7. The medical device of claim 1 wherein said polymeric waxis branched.
 8. The medical device of claim 1 wherein said polymeric waxcomprises a copolymer.
 9. The medical device of claim 9 wherein said waxcopolymer comprises the reaction product of said polybasic acid orderivative thereof, a monoglyceride selected from the group consistingof monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoylglycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroylglycerol, monolinoleoyl glycerol and monooleoyl glycerol, and at leastone additional polyol selected from the group consisting of ethyleneglycol, 1,2-propylene glycol, 1,3-propanediol, bis-2-hydroxyethyl ether,1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol,1,10-decanediol, 1,12-dodecanediol, other diols, linear poly(ethyleneglycol), branched poly(ethylene glycol), linear poly(propylene glycol),branched poly(propylene glycol), linear poly(ethylene-co-propyleneglycol)s and branched poly(ethylene-co-propylene glycol)s.
 10. Themedical device of claim 1 further comprising an aliphatic polyesterprepared from monomers selected from the group consisting of glycolide,L-lactide, D-lactide, meso-lactide, rac-lactide, ε-caprolactone,trimethylene carbonate, p-dioxanone, 1,4-dioxanone, 1,4-dioxepan-2-one,1,5-dioxepan-2-one and substituted derivatives thereof.
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